1. Field of the Invention
The present invention relates to halogenated amidino amino acid derivatives and their use in therapy, in particular their use as nitric oxide synthase inhibitors.
2. Discussion of the Prior Art
It has been known since the early 1980""s that the vascular relaxation caused by acetylcholine is dependent on the presence of the vascular endothelium and this activity was ascribed to a labile humoral factor termed endothelium-derived relaxing factor (EDRF). The activity of nitric oxide (NO) as a vasodilator has been known for well over 100 years. In addition, NO is the active component of amylnitrite, glyceryltrinitrate and other nitrovasodilators. The recent identification of EDRF as NO has coincided with the discovery of a biochemical pathway by which NO is synthesized from the amino acid L-arginine by the enzyme NO synthase.
Nitric oxide is the endogenous stimulator of the soluble guanylate cyclase. In addition to endothelium-dependent relaxation, NO is involved in a number of biological actions including cytotoxicity of phagocytic cells and cell-to-cell communication in the central nervous system (see Moncada et al., Biochemical Pharmacology, 38, 1709-1715, 1989; Moncada et al., Pharmacological Reviews, 43, 109-142, 1991). Excess NO production appears to be involved in a number of pathological conditions, particularly conditions which involve systemic hypotension such as toxic shock, septic shock and therapy with certain cytokines (Kerwin et al., J. Medicinal Chemistry, 38, 4343-4362, 1995).
The synthesis of NO from L-arginine can be inhibited by the L-arginine analogue, L-N-monomethyl-arginine (L-NMMA) and the therapeutic use of L-NMMA for the treatment of toxic shock and other types of systemic hypotension has been proposed (WO 91/04024 and GB-A-2240041). The therapeutic use of certain other NO synthase inhibitors apart from L-NMMA for the same purpose has also been proposed in WO 91/04024 and in EP-A-0446699.
It has recently become apparent that there are at least three types of NO synthase as follows:
(i) a constitutive, Ca++/calmodulin dependent enzyme, located in the endothelium, that releases NO in response to receptor or physical stimulation.
(ii) a constitutive, Ca++/calmodulin dependent enzyme, located in the brain, that releases NO in response to receptor or physical stimulation.
(iii) a Ca++ independent enzyme which is induced after activation of vascular smooth muscle, macrophages, endothelial cells, and a number of other cells by endotoxin and cytokines. Once expressed this inducible NO synthase generates NO continuously for long periods.
The NO released by the two constitutive enzymes acts as a transduction mechanism underlying several physiological responses. The NO produced by the inducible enzyme is a cytotoxic molecule for tumor cells and invading microorganisms. It also appears that the adverse effects of excess NO production, in particular pathological vasodilation and tissue damage, may result largely from the effects of NO synthesized by the inducible NO synthase (Knowles and Moncada, Biochem J., 298, 249-258, 1994 Billiar et al., Annals of Surgery, 221, 339-349, 1995; Davies et al., 1995).
There is also a growing body of evidence that NO may be involved in the degeneration of cartilage which takes place in certain conditions such as arthritis and it is also known that NO synthesis is increased in rheumatoid arthritis and in osteoarthritis (McInnes et al., J. Exp. Med, 184, 1519-1524, 1996; Sakurai et al., J. Clin. Investig., 96, 2357-2363, 1995). Accordingly, conditions in which there is an advantage in inhibiting NO production from L-arginine include autoimmune and/or inflammatory conditions affecting the joints, for example arthritis, and also inflammatory bowel disease, cardivascular ischemia, diabetes, diabetic retinopathy, nephropathy, cardiomyopathy, congestive heart failure, myocarditis, atherosclerosis, migraine, reflux esophagitis, diarrhea, irritable bowel syndrome, cystic fibrosis, emphysema, asthma, chronic obstructive pulmonary disease, bronchiectasis, herniated vertebral discs, obesity, psoriasis, rosacea, contact dermatitis, hyperalgesia (allodynia), cerebral ischemia [both focal ischemia, thrombotic stroke and global ischemia (secondary to cardiac arrest)], anxiety multiple sclerosis and other central nervous system disorders mediated by NO, for example Parkinson""s disease and Alzheimer""s disease, rhinitis, cancer therapy, and other disorders mediated by NO including opiate tolerance in patients needing protracted opiate analgesics, and benzodiazepine tolerance in patients taking benzodiazepines, and other addictive behavior, for example, nicotine and eating disorders (Kerwin et al., J. Medicinal Chemistry, 38, 4343-4362, 1995; Knowles and Moncada, Biochem J., 298, 249-258, 1994; Davies et al., 1995; Pfeilschifter et al., Cell Biology International, 20, 51-58, 1996).
Further conditions in which there is an advantage in inhibiting NO production from L-arginine include systemic hypotension associated with septic and/or toxic shock induced by a wide variety of agents; therapy with cytokines such as TNF, IL-1 and IL-2; and as an adjuvant to short term immunosuppression in transplant therapy (E. Kelly et al., J. Partent. Ent. Nutri., 19, 234-238, 1995; S. Moncada and E. Higgs, FASEB J., 9, 1319-1330, 1995; R. G. Kilbourn et al, Crit. Care Med., 23, 1018-1024, 1995).
More recently, NO has been identified as being a neurotransmitter in pain pathways of the spinal cord. The administration of NO synthase inhibitors in patients with cronic pain syndromes, and more specifically cronic tension-type headaches, has been shown to reduce the level of pain. (The Lancet, 353:256-257, 287-289, 1999)
Some of the NO synthase inhibitors proposed for therapeutic use so far, and in particular L-NMMA, are non-selective; they inhibit both the constitutive and the inducible NO synthases. Use of such a non-selective NO synthase inhibitor requires that great care be taken in order to avoid the potentially serious consequences of over-inhibition of the constitutive NO-synthase including hypertension and possible thrombosis and tissue damage. In particular, in the case of the therapeutic use of L-NMMA for the treatment of toxic shock it has been recommended that the patient must be subject to continuous blood pressure monitoring throughout the treatment. Thus, while non-selective NO synthase inhibitors have therapeutic utility provided that appropriate precautions are taken, NO synthase inhibitors which are selective in the sense that they inhibit the inducible NO synthase to a considerably greater extent than the constitutive isoforms of NO synthase would be of even greater therapeutic benefit and easier to use (S. Moncada and E. Higgs, FASEB J., 9, 1319-1330, 1995). WO 96/35677, WO 96/33175, WO 96/15120, WO 95/11014, WO 95/11231 WO 95/25717, WO 95/24382, WO94/12165, WO94/14780, WO93/13055, EP0446699A1 and U.S. Pat. No. 5,132,453 disclose compounds that inhibit nitric oxide synthesis and preferentially inhibit the inducible isoforms of nitric oxide synthase. The disclosures of which are hereby incorporated by reference in their entirety as if written herein.
In a broad aspect, the present invention is directed to inhibiting or modulating nitric oxide synthesis in a subject in need of such inhibition or modulation by administering a compound which preferentially inhibits or modulates the inducible isoform of nitric oxide synthase over the constitutive isoforms of nitric oxide synthase. It is also another object of the present invention to lower nitric oxide levels in a subject in need of such lowering.
The present invention is directed to the halogenation of amidino amino acid derivatives to exhibit iNOS inhibition activity and bioactivity. Halogenation alters the basicity of the amidine moiety, and increases potency and provides a longer half-life in vivo as iNOS inhibitors.
Compounds of the present invention are represented by halogenated amidino compounds of formula (I): 
or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from the group consisting of hydrogen, C1-C10 alkyl, C2-C10 alkenyl, and C2-C10 alkynyl;
R2 is selected from the group consisting of hydrogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, and either R or S alpha-amino acid;
R3 and R4 are independently selected from the group consisting of hydrogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, and NO2;
wherein R1, R2, R3 and R4 can be optionally substituted from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano, nitro, amino, carboxy, carboxyalkyl, carboxyaryl, amidino, and guanidino;
R11 is selected from the group consisting of hydroxyl and R or S alpha-amino acid;
G is selected from the group consisting of C1-C10 alkylene, C2-C10 alkenylene, and C2-C10 alkynylene, each of which is optionally substituted with one or more selected from the group consisting of halogen, hydroxy, trifluoromethyl, nitro, cyano, amino, C1-C10 alkyl, xe2x95x90CH2, C2-C10 alkenyl, C2-C10 alkynyl, and C1-C10 alkoxy, each of which can be can be optionally substituted from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano, nitro, amino, carboxy, carboxyalkyl, carboxyaryl, amidino, guanidino, trifluoromethyl, and nitro;
G is selected from the formula (CH2)pxe2x80x94(CX1X2)rxe2x80x94(CH2)sxe2x80x94Qxe2x80x94(CH2)txe2x80x94(CX3X4)uxe2x80x94(CH2)v where p, r, s, t, u, v are independently 0 to 3 and Q is oxygen, Cxe2x95x90O, S(O)a wherein a is 0 to 2, with the proviso that when a is 1 or 2, G must contain halogen, or NR12 wherein R12 is hydrogen or C1-C10 alkyl which may be optionally substituted with one or more selected from the group consisting of C1-C10 alkyl, C1-C10 alkoxy, hydroxy, trifluoromethyl, nitro, cyano, amino, and halogen;
G is selected from the formula xe2x80x94(CH2)wxe2x80x94(CX5X6)yxe2x80x94(CH2)zxe2x80x94Axe2x80x94(CH2)kxe2x80x94(CX7X8)jxe2x80x94(CH2)h wherein w, y, z, k, j, h are independently 0 to 3 and A is a 3 to 6 membered carbocyclic radical or heterocyclic radical which may be optionally substituted with one or more selected from the group consisting of halogen, C1-C10 alkyl, C1-C10 alkoxy, hydroxy, trifluoromethyl, nitro, cyano, and amino, each of which may be optionally substituted with halogen or C1-C10 alkyl, with the proviso that when G is selected from the formula xe2x80x94(CH2)wxe2x80x94(CX5X6)yxe2x80x94(CH2)zxe2x80x94Axe2x80x94(CH2)kxe2x80x94(CX7X8)jxe2x80x94(CH2)h, Y must contain halogen;
X1, X2, X3, X4, X5, X6, X7, X8 are independently not present, hydrogen, halogen, C1-C10 alkyl, xe2x95x90CH2, C2-C10 alkenyl, or C2-C10 alkynyl, wherein C1-C10 alkyl, xe2x95x90CH2, C2-C10 alkenyl, and C2-C10 alkynyl can be optionally substituted with one or more from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano, nitro, amino, carboxy, carboxyalkyl, carboxyaryl, amidino, guanidino, trifluoromethyl, and nitro;
Y is selected from the group consisting of heterocycle, C1-C10 haloalkyl, C1-C10 dihaloalkyl, C1-C10 trihaloalkyl, C1-C10 alkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, and C2-C10 alkynyl, each of which is optionally substituted with one or more selected from the group consisting of halogen, hydroxy, trifluoromethyl, nitro, cyano, amino, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, and C1-C10 alkoxy;
Y can be NR9R10 wherein R9 and R10 are independently selected from the group consisting of hydrogen, C1-C10 alkyl, C3-C1l cycloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, nitro, amino, aryl, and C1-C10 alkaryl;
with the proviso that at least one of G or Y contains a halogen.
Compounds of the present invention can exist in geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-geometric isomers, E- and Z-geometric isomers, R- and S-enantiomers, diastereomers, d-isomers, l-isomers, the racemic mixtures thereof and other mixtures thereof, as falling within the scope of the invention.
It is an object of the present invention to provide compounds that have usefulness as inhibitors of nitric oxide synthase. These compounds also preferentially inhibit the inducible form over the constitutive form by at least 3 fold.
It is also an object of the present invention to provide compounds that are more selective than those known in the art.
Preferably, compounds of the present invention are halogenated amidino compounds of formula (I) wherein: 
or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from the group consisting of hydrogen, C1-C10 alkyl, C2-C10 alkenyl, and C2-C10 alkynyl;
R2 is selected from the group consisting of hydrogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, and either R or S alpha-amino acid;
R3 and R4 are independently selected from the group consisting of hydrogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, and NO2;
wherein R1, R2, R3 and R4 can be optionally substituted from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano, nitro, amino, carboxy, carboxyalkyl, carboxyaryl, amidino, and guanidino;
R11 is selected from the group consisting of hydroxyl and R or S alpha-amino acid;
G is selected from the group consisting of C1-C10 alkylene, C2-C10 alkenylene, and C2-C10 alkynylene, each of which is optionally substituted with one or more selected from the group consisting of halogen, hydroxy, trifluoromethyl, nitro, cyano, amino, C1-C10 alkyl, xe2x95x90CH2, C2-C10 alkenyl, C2-C10 alkynyl, and C1-C10 alkoxy, each of which can be can be optionally substituted from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano, nitro, amino, carboxy, carboxyalkyl, carboxyaryl, amidino, guanidino, trifluoromethyl, and nitro;
G is selected from the formula (CH2)pxe2x80x94(CX1X2 )rxe2x80x94(CH2)sxe2x80x94Qxe2x80x94(CH2)txe2x80x94(CX3X4)uxe2x80x94(CH2), where p, r, s, t, u, v are independently 0 to 3 and Q is oxygen, Cxe2x95x90O, S(O)a wherein a is 0 to 2, with the proviso that when a is I or 2, G must contain halogen, or NR12 wherein R12 is hydrogen or C1-C10 alkyl which may be optionally substituted with one or more selected from the group consisting of C1-C10 alkyl, C1-C10 alkoxy, hydroxy, trifluoromethyl, nitro, cyano, amino, and halogen;
G is selected from the formula xe2x80x94(CH2)wxe2x80x94(CX5X6)yxe2x80x94(CH2)zxe2x80x94Axe2x80x94(CH2)kxe2x80x94(CX7X8)jxe2x80x94(CH2)h wherein w, y, z, k, j, h are independently 0 to 3 and A is a 3 to 6 membered carbocyclic radical or heterocyclic radical which may be optionally substituted with one or more selected from the group consisting of halogen, C1-C10 alkyl, C1-C10 alkoxy, hydroxy, trifluoromethyl, nitro, cyano, and amino, each of which may be optionally substituted with halogen or C1-C10 alkyl, with the proviso that when G is selected from the formula xe2x80x94(CH2)wxe2x80x94(CX5X6)yxe2x80x94(CH2)zxe2x80x94Axe2x80x94(CH2)kxe2x80x94(CX7X8)jxe2x80x94(CH2)h, Y must contain halogen;
X1, X2, X3, X4, X5, X6, X7, X8 are independently not present, hydrogen, halogen, C1-C10 alkyl, xe2x95x90CH2, C2-C10 alkenyl, or C2-C10 alkynyl, wherein C1-C10 alkyl, xe2x95x90CH2, C2-C10 alkenyl, and C2-C10 alkynyl can be optionally substituted with one or more from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano, nitro, amino, carboxy, carboxyalkyl, carboxyaryl, amidino, guanidino, trifluoromethyl, and nitro;
Y is selected from the group consisting of heterocycle, C1-C10 haloalkyl, C1-C10 dihaloalkyl, C1-C10 trihaloalkyl, C1-C10 alkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, and C2-C10 alkynyl, each of which is optionally substituted with one or more selected from the group consisting of halogen, hydroxy, trifluoromethyl, nitro, cyano, amino, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, and C1-C10 alkoxy;
Y can be NR9R10 wherein R9 and R10 are independently selected from the group consisting of hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, nitro, amino, aryl, and C1-C10 alkaryl;
with the proviso that at least one of G or Y contains a halogen.
More preferably, compounds of the present invention are of the formula (I) wherein;
G is selected from the formula (CH2)pxe2x80x94(CX1X2)rxe2x80x94(CH2)sxe2x80x94Qxe2x80x94(CH2)txe2x80x94(CX3X4)uxe2x80x94(CH2), where p, r, s, t, u, v are independently 0-3 and Q is oxygen, Cxe2x95x90O, S(O)a wherein a is 0 to 2, with the proviso that when a is 1 or 2, G must contain a halogen, or NR12 wherein R12 is hydrogen or C1-C10 alkyl, which may be optionally substituted with one or more selected from the group consisting of C1-C10 alkyl, C1-C10 alkoxy, hydroxy, trifluoromethyl, nitro, cyano, amino, and halogen; and
Y is selected from the group consisting of C1-C10 haloalkyl, C1-C10 dihaloalkyl, C1-C10 trihaloalkyl, C1-C10 alkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, and C2-C10 alkynyl.
More preferably, compounds of the present invention are of the formula (I):
wherein:
R1, R2 are H,
R3, R4 are independently H, or NO2;
G is selected from the formula (CH2)pxe2x80x94(CX1X2)rxe2x80x94(CH2)sxe2x80x94Qxe2x80x94(CH2)txe2x80x94(CX3X4)uxe2x80x94(CH2)v where p, r, s, t, u, v are independently 0-3 and Q is oxygen, Cxe2x95x90O, S(O)a wherein a is 0 to 2, with the proviso that when a is 1 or 2, G must contain a halogen, or NR12 wherein R12 is hydrogen or C1-C10 alkyl, which may be optionally substituted with one or more selected from the group consisting of C1-C10 alkyl, C1-C10 alkoxy, hydroxy, trifluoromethyl, nitro, cyano, amino, and halogen; and
Y is selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each of which is optionally substituted with one or more halogens, or NHR9 wherein R9 is hydrogen, C1-C6 alkyl C3-C6 cycloalkyl, C2-C6 alkenyl, or C2-C6 alkynyl.
More preferably, compounds of the present invention are of the formula (I):
wherein:
R1, R2, R3 and R4 are H; and
Y is C1-C6 alkyl optionally substituted with at least one halogen.
Most preferably, compounds of the present invention are selected from the group consisting of:
N-(2-fluoro-1-iminoethyl)-3-aminoethyl-L-cysteine dihydrochloride;
N-(2-fluoro-1-iminoethyl)-2-aminoethyl-L-cysteine dihydrochloride;
N-(2-fluoro-1-iminoethyl)-2-aminoethyl-D,L-homocysteine dihydrochloride; and
N-(2-fluoro-1-iminoethyl)-2-aminoethyl-L-homocysteine dihydrochloride.
As utilized herein, the term xe2x80x9calkylxe2x80x9d, alone or in combination, means a branched or unbranched acyclic alkyl radical containing from 1 to 10, preferably from 1 to 8 carbon atoms and more preferably 1 to 6 carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like.
The term xe2x80x9calkenylxe2x80x9d refers to a branched or unbranched unsaturated acyclic hydrocarbon radical in so much as it contains at least one double bond. Such radicals containing from 2 to 10 carbon atoms, preferably from 2 to 8 carbon atoms and more preferably 2 to 6 carbon atoms. Examples of suitable alkenyl radicals include propylenyl, buten-1-yl, isobutenyl, pentenylen-1-yl, 2-2-methylbuten-1-yl, 3-methylbuten-1-yl, hexen-1-yl, hepten-1-yl, and octen-1-yl, and the like.
The term xe2x80x9calkynylxe2x80x9d refers to a branched or unbranched unsaturated acyclic hydrocarbon radical in so much as it contains one or more triple bonds. Such radicals containing 2 to 10 carbon atoms, preferably having from 2 to 8 carbon atoms and more preferably having 2 to 6 carbon atoms. Examples of suitable alkynyl radicals include ethynyl, propynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 3-methylbutyn-1-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl, 3,3-dimethylbutyn-1-yl radicals and the like.
The term xe2x80x9cheterocyclic radicalxe2x80x9d means an unsaturated cyclic hydrocarbon radical with 3 to about 6 carbon atoms, wherein 1 to about 4 carbon atoms are replaced by nitrogen, oxygen or sulfur. The xe2x80x9cheterocyclic radicalxe2x80x9d may be fused to an aromatic hydrocarbon radical. Suitable examples include pyrrolyl, pyridinyl, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl, tetrazolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, 1,3-dioxolanyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, benzo(b)thiophenyl, benzimidazonyl, quinolinyl, and the like.
The term xe2x80x9carylxe2x80x9d means an aromatic hydrocarbon radical of 4 to 16 carbon atoms, preferably 6 to about 12 carbon atoms, more preferably 6 to 10 carbon atoms. Examples of suitable aromatic hydrocarbon radicals include phenyl, naphthyl, and the like.
The terms xe2x80x9ccycloalkylxe2x80x9d or xe2x80x9ccycloalkenylxe2x80x9d means an xe2x80x9calicyclic radical in a ring with 3 to 10 carbon atoms, and preferably from 3 to 6 carbon atoms. Examples of suitable alicyclic radicals include cyclopropyl, cyclopropylenyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-cyclohexen-1-ylenyl, cyclohexenyl and the like.
The term xe2x80x9calkoxyxe2x80x9d, alone or in combination, means an alkyl ether radical wherein the term alkyl is as defined above and most preferably containing 1 to 4 carbon atoms. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.
The term xe2x80x9calkylenexe2x80x9d refers to hydrocarbons containing 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, and more preferably 1 to 6 carbon atoms.
The term xe2x80x9calkenylenexe2x80x9d and xe2x80x9calkynylenexe2x80x9d refers to hydrocarbons containing 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, and more preferably 2 to 6 carbon atoms.
The term xe2x80x9chalogenxe2x80x9d means fluorine, chlorine, bromine or iodine.
The term xe2x80x9cprodrugxe2x80x9d refers to a compound that is made more active in vivo.
As used herein, reference to xe2x80x9ctreatmentxe2x80x9d of a patient is intended to include prophylaxis.
The present invention includes compounds of formula (I) in the form of salts, in particular acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable although salts of non-pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question. Thus, preferred salts include those formed from hydrochloric, hydrobromic, sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, succinic, oxalic, fumaric, maleic, oxaloacetic, methanesulphonic, ethanesulphonic, toluenesulphonic, benzenesulphonic and isethionic acids. Salts of the compounds of formula (I) can be made by reacting the appropriate compound in the form of the free base with the appropriate acid.
While it may be possible for the compounds of formula (I) to be administered as the raw chemical, it is preferable to present them as a pharmaceutical composition. According to a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients. The carrier(s) must be xe2x80x9cacceptablexe2x80x9d in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), via inhalation rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (xe2x80x9cactive ingredientxe2x80x9d) with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline, water-for-injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter or polyethylene glycol.
Formulations for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
Preferred unit dosage formulations are those containing an effective dose, as hereinbelow recited, or an appropriate fraction thereof, of the active ingredient.
It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
The compounds of the invention may be administered orally or via injection at a dose of from 0.001 to 2500 mg/kg per day. The dose range for adult humans is generally from 0.005 mg to 10 g/day. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound of the invention which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.
The compounds of formula (I) are preferably administered orally or by injection (intravenous or subcutaneous). The precise amount of compound administered to a patient will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity. Also, the route of administration may vary depending on the condition and its severity.
All references, patents or applications, U.S. or foreign, cited in the application are hereby incorporated by reference as if written herein.
The following are general synthetic sequences which are useful in making the compounds of the present invention. 